A genetic study based on PCNA-ubiquitin fusions reveals no requirement for PCNA polyubiquitylation in DNA damage tolerance

Gervai, Judit; Gálicza, Judit; Szeltner, Zoltán; Zámborszky, Judit; Szüts, Dávid

doi:10.1016/j.dnarep.2017.04.003

Cited by 14 publications

(14 citation statements)

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“…These observations indicate that a TLS defect caused by pol g-deficiency, but not those due to REV1or REV3-deficiencies, does not reroute TT-CPD lesions to the HDR pathway (Varga et al 2012;Gervai et al 2017). Interestingly, HDR-dependent TT-CPD processing is reduced in XRCC3-or BRCA1-deficient cells (Gervai et al 2017). These observations suggest that HDR is regulated by XRCC3 and BRCA1 independent of PCNA modification at K164 (Varga et al 2012;Gervai et al 2017).…”

Section: Choice and Switching Between The Tls And Hdr Ddt Pathwaysmentioning

confidence: 88%

“…By contrast, in REV1-or REV3deficient cells, the fraction processed by TLS decreased to approximately half of that of the wild-type cells with a concomitant increase in the fraction processed by HDR. These observations indicate that a TLS defect caused by pol g-deficiency, but not those due to REV1or REV3-deficiencies, does not reroute TT-CPD lesions to the HDR pathway (Varga et al 2012;Gervai et al 2017). Interestingly, HDR-dependent TT-CPD processing is reduced in XRCC3-or BRCA1-deficient cells (Gervai et al 2017).…”

Section: Choice and Switching Between The Tls And Hdr Ddt Pathwaysmentioning

confidence: 91%

“…In mammals, TLS does not absolutely require PCNA monoubiquitination (Langerak et al 2007;Roa et al 2008;Krijger et al 2009;Acharya et al 2010;Hendel et al 2011;Temviriyanukul et al 2012;Masuda et al 2015;Wit et al 2015), a conclusion also supported by in vitro reconstitution experiments (Masuda et al 2010;Hedglin et al 2016). In chicken DT40 cells, it is less important (Okada et al 2002;Ross et al 2005;Arakawa et al 2006;Edmunds et al 2008;Sz€ uts et al 2008;Varga et al 2012;Gervai et al 2017;Z amborszky et al 2017). Interestingly, in the fission yeast Schizosaccharomyces pombe (S. pombe), polyubiquitinated PCNA stimulates TLS more efficiently than does monoubiquitinated PCNA (Coulon et al 2010).…”

Section: Introductionmentioning

confidence: 94%

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Spatiotemporal regulation of PCNA ubiquitination in damage tolerance pathways

Masuda

Masutani

2019

Critical Reviews in Biochemistry and Molecular Biology

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DNA is constantly exposed to a wide variety of exogenous and endogenous agents, and most DNA lesions inhibit DNA synthesis. To cope with such problems during replication, cells have molecular mechanisms to resume DNA synthesis in the presence of DNA lesions, which are known as DNA damage tolerance (DDT) pathways. The concept of ubiquitination-mediated regulation of DDT pathways in eukaryotes was established via genetic studies in the yeast Saccharomyces cerevisiae, in which two branches of the DDT pathway are regulated via ubiquitination of proliferating cell nuclear antigen (PCNA): translesion DNA synthesis (TLS) and homology-dependent repair (HDR), which are stimulated by mono-and polyubiquitination of PCNA, respectively. Over the subsequent nearly two decades, significant progress has been made in understanding the mechanisms that regulate DDT pathways in other eukaryotes. Importantly, TLS is intrinsically error-prone because of the miscoding nature of most damaged nucleotides and inaccurate replication of undamaged templates by TLS polymerases (pols), whereas HDR is theoretically error-free because the DNA synthesis is thought to be predominantly performed by pol d, an accurate replicative DNA pol, using the undamaged sister chromatid as its template. Thus, the regulation of the choice between the TLS and HDR pathways is critical to determine the appropriate biological outcomes caused by DNA damage. In this review, we summarize our current understanding of the species-specific regulatory mechanisms of PCNA ubiquitination and how cells choose between TLS and HDR. We then provide a hypothetical model for the spatiotemporal regulation of DDT pathways in human cells.

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Section: Choice and Switching Between The Tls And Hdr Ddt Pathwaysmentioning

confidence: 88%

Section: Choice and Switching Between The Tls And Hdr Ddt Pathwaysmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 94%

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Spatiotemporal regulation of PCNA ubiquitination in damage tolerance pathways

Masuda

Masutani

2019

Critical Reviews in Biochemistry and Molecular Biology

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“…In the budding yeast Saccharomyces cerevisiae , there are three major strategies to maintain genome stability: template switch (TS) (7), homologous recombination (HR) (8), and TLS (9). TS is an error-free damage branch of the DNA damage tolerance mechanism, which is regulated by the polyubiquitination of proliferating cell nuclear antigen (PCNA) catalyzed by the Ubc13 and Mms2 enzymes (7,10,11). HR mainly repairs DNA double-strand breaks and is regulated by Srs2 and Rad51 (11).…”

Section: Introductionmentioning

confidence: 99%

Lsm12 mediates Pol·q deubiquitination to help Saccharomyces cerevisiae resist oxidative stress

Yao

Shi²,

Chen

et al. 2018

Preprint

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15In Saccharomyces cerevisiae, the Y-family DNA polymerase η (Polη) regulates genome stability 16 in response to different forms of environmental stress by translesion DNA synthesis. To elucidate 17 the role of Polη in oxidative stress-induced DNA damage, we deleted or overexpressed the 18 corresponding gene RAD30, and used transcriptome analysis to screen the potential genes 19 associated with RAD30 to respond to DNA damage. Under 2 mM H 2 O 2 , deletion of RAD30 20 resulted in a 2.2-fold decrease in survival and a 2.8-fold increase in DNA damage, whereas 21 overexpression of RAD30 increased survival and decreased DNA damage by 1.2-and 1.4-fold, 22 IMPORTANCE 34Polη was shown to be critical for cell growth in the yeast Saccharomyces cerevisiae, and deletion 35 of its corresponding gene RAD30 caused a severe growth defect under exposure to oxidative 36 stress with 2 mM H 2 O 2 . Furthermore, we found that Lsm12 physically interacts with Polη and 37 promotes Polη deubiquitination and recruitment. Overall, these findings indicate Lsm12 as a 38 novel regulator mediating Polη deubiquitination that regulates its recruitment in response to 39 DNA damage induced by oxidative stress. 40

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“…damage branch of the DNA damage tolerance mechanism, which is regulated by the polyubiquitination of proliferating cell nuclear antigen (PCNA) catalyzed by the Ubc13 and Mms2 enzymes (7,10,11). HR mainly repairs DNA double-strand breaks and is regulated by Srs2 and Rad51 (11).…”

mentioning

confidence: 99%

Lsm12 Mediates Deubiquitination of DNA Polymerase η To Help Saccharomyces cerevisiae Resist Oxidative Stress

Yao

Shi

et al. 2019

Appl Environ Microbiol

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In Saccharomyces cerevisiae, the Y family DNA polymerase (Pol) regulates genome stability in response to different forms of environmental stress by translesion DNA synthesis. To elucidate the role of Pol in oxidative stress-induced DNA damage, we deleted or overexpressed the corresponding gene RAD30 and used transcriptome analysis to screen the potential genes associated with RAD30 to respond to DNA damage. Under 2 mM H 2 O 2 treatment, the deletion of RAD30 resulted in a 2.2-fold decrease in survival and a 2.8-fold increase in DNA damage, whereas overexpression of RAD30 increased survival and decreased DNA damage by 1.2-and 1.4-fold, respectively, compared with the wild-type strain. Transcriptome and phenotypic analyses identified Lsm12 as a main factor involved in oxidative stress-induced DNA damage. Deleting LSM12 caused growth defects, while its overexpression enhanced cell growth under 2 mM H 2 O 2 treatment. This effect was due to the physical interaction of Lsm12 with the UBZ domain of Pol to enhance Pol deubiquitination through Ubp3 and consequently promote Pol recruitment. Overall, these findings demonstrate that Lsm12 is a novel regulator mediating Pol deubiquitination to promote its recruitment under oxidative stress. Furthermore, this study provides a potential strategy to maintain the genome stability of industrial strains during fermentation. IMPORTANCE Pol was shown to be critical for cell growth in the yeast Saccharomyces cerevisiae, and deletion of its corresponding gene RAD30 caused a severe growth defect under exposure to oxidative stress with 2 mM H 2 O 2 . Furthermore, we found that Lsm12 physically interacts with Pol and promotes Pol deubiquitination and recruitment. Overall, these findings indicate Lsm12 is a novel regulator mediating Pol deubiquitination that regulates its recruitment in response to DNA damage induced by oxidative stress.

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A genetic study based on PCNA-ubiquitin fusions reveals no requirement for PCNA polyubiquitylation in DNA damage tolerance

Abstract: Post-translational modifications of Proliferating Cell Nuclear Antigen (PCNA) play a key role in regulating the bypass of DNA lesions during DNA replication. PCNA can be monoubiquitylated at lysine 164 by the RAD6-RAD18 ubiquitin ligase complex.

Cited by 14 publications

References 54 publications

Spatiotemporal regulation of PCNA ubiquitination in damage tolerance pathways

Spatiotemporal regulation of PCNA ubiquitination in damage tolerance pathways

Lsm12 mediates Pol·q deubiquitination to help Saccharomyces cerevisiae resist oxidative stress

Lsm12 Mediates Deubiquitination of DNA Polymerase η To Help Saccharomyces cerevisiae Resist Oxidative Stress

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